Dimethylamino Parthenolide Enhances the Inhibitory Effects of Gemcitabine in Human Pancreatic Cancer Cells

作者：Holcomb Bryan K; Yip Schneider Michele T^*; Waters Joshua A; Beane Joal D; Crooks Peter A; Schmidt C Max

来源：Journal of Gastrointestinal Surgery, 2012, 16(7): 1333-1340.

DOI：10.1007/s11605-012-1913-7

• Pancreatic cancer
• NF-kappa B
• DMAPT
• Parthenolide and gemcitabine

Gemcitabine is standard treatment for pancreatic cancer but has limited clinical benefit due to chemoresistance. Nuclear factor-kappaB (NF-kappa B) can promote chemoresistance and is therefore an attractive therapeutic target. We hypothesize that NF-kappa B suppression with the novel, orally bioavailable inhibitor dimethylamino parthenolide (DMAPT) will sensitize pancreatic cancer cells to gemcitabine. %26lt;br%26gt;BxPC-3, PANC-1, and MIA PaCa-2 human pancreatic cancer cell lines were treated with gemcitabine and/or DMAPT. Effects on the NF-kappa B pathway were determined by electrophoretic mobility shift assay, ELISA, or Western blot. Proliferation and apoptosis were measured by cell counts and ELISA, respectively. The effect of gemcitabine in vivo was determined using a MIA PaCa-2 heterotopic xenograft model. %26lt;br%26gt;Gemcitabine induced NF-kappa B activity in BxPC-3, PANC-1, and MIA PaCa-2 cells and decreased the level of the NF-kappa B inhibitor I kappa B alpha in BxPC-3 and PANC-1 cells. DMAPT prevented the gemcitabine-induced activation of NF-kappa B. The combination of DMAPT/gemcitabine inhibited pancreatic cancer cell growth more than either agent alone. Gemcitabine also induced intratumoral NF-kappa B activity in vivo. %26lt;br%26gt;DMAPT enhanced the anti-proliferative effects of gemcitabine in association with NF-kappa B suppression in pancreatic cancer cells in vitro. Furthermore, gemcitabine induced NF-kappa B activity in vivo, thus supporting the evaluation of NF-kappa B-targeted agents to complement gemcitabine-based therapies.

• 出版日期2012-7